Ir-catalyzed highly selective addition of pyridyl C–H bonds to aldehydes promoted by triethylsilane

Abstract

We report herein an iridium-catalyzed activation of pyridine C–H bond and its nucleophilic addition to benzaldehydes. The reaction was applicable to various pyridine derivatives and aryl aldehydes. In contrast to most methods that selectively functionalize the C2 pyridine C–H bond, this reaction proceeded with unusual meta-selectivity. An independently synthesized silyl iridium complex was able to catalyze the reaction, indicating that a silyl iridium intermediate might be responsible for the novel reactivity and the unusual selectivity.

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Introduction

Nucleophilic addition of aryl Grignard reagents to carbonyl compounds is a fundamentally important reaction, which has been well developed and broadly utilized in alcohol synthesis.¹ An inherent limitation of this traditional process is the requirement of using organohalides as the starting materials, since the preparation of organohalides commonly requires tedious procedures and causes environmental problems. As a valuable complementary method, Snieckus's directed orthometallation (DoM) employs arenes as substrates, which is advantageous from a synthetic point of view.² However, both Grignard reaction and Snieckus's chemistry involve the manipulation of air- and moisture-sensitive main group organometallic reagents, as well as produce salt wastes.

To overcome these issues, direct utilization of aromatic C–H bonds as the surrogates of main-group organometallic reagents such as Grignard reagents would be highly appealing (Scheme 1). Despite the recent achievements made in direct C–H functionalization,³ transition-metal catalyzed direct addition of an aromatic C–H bond to a carbonyl group through C–H functionalization has rarely been reported.^4–7 Murai and co-workers first reported an iridium-catalyzed coupling of imidazole with aliphatic aldehydes, in which C–H activation was not involved in the proposed mechanism.⁴ Later on, Takai and co-workers developed the elegant Re- and Mn-catalyzed addition of aromatic C–H bonds to aldehydes by using directing group assisted strategy.⁵ Recently, Shibata and co-workers described a cationic iridium-catalyzed intramolecular addition of aromatic C–H bonds to ketones, which provided an efficient method to synthesize useful benzofurans and indoles.⁶ Despite these significant achievements, the limited substrate scope, restrained ortho selectivity, and/or the requirement of a directing group substantially hampered the practicability of these novel reactions. Therefore, the development of an efficient catalytic system that enables diversified substrate scope and different selectivity would be of profound interest in this area.

Scheme 1 C–H substrate as Grignard reagent surrogate.

Pyridine is an important structural unit and widely exists in natural products and medicinally relevant compounds.⁸ Consequently, a diverse range of catalytic methods have been developed to directly functionalize pyridine derivatives through C–H activation.⁹ However, most of these functionalization processes occurred regioselectively at the C2 position. Although a number of groups reported intramolecular C3 and C4 arylation of pyridine derivatives,^10a to the best of our knowledge, the intermolecular C–H activation/C–C formation at C3 or C4 position of pyridine without activating or directing groups has never been achieved.^10,11 Herein, we report the first example of an Ir-catalyzed nucleophilic addition of pyridine derivatives to aldehydes through C–H activation with unusual meta selectivity (Scheme 2).¹² From a synthetic point of view, a meta-selective addition of pyridine to aldehydes is highly desirable since metallation of pyridine with main-group and early transition metals (Li, Mg, Mn, etc) always occurs at the ortho-position, and a meta-metallation is notoriously difficult.^2e

Scheme 2 Meta-selective functionalization of pyridine.

Results and discussion

Initial studies

3-Phenylpyridine 1a was first selected to explore the suitable reaction conditions (Table 1). Although several metal complexes, including Mn, Re, Ru and Rh, showed good reactivities in many direct C–H transformations,³ they completely failed after many trials (entries 1–5). To our delight, an iridium complex [Ir(COD)Cl]₂ promoted the addition of the meta pyridyl C–H bond to benzaldehyde in the presence of triethylsilane in benzene (entry 6). The product was obtained as a triethylsilyl-protected benzyl alcohol. Other iridium complexes such as [Ir(COD)(OMe)]₂ and [Cp*IrCl₂]₂, however, gave no product at all (entries 7 and 8). To our satisfaction, an iridium carbonyl complex Ir₄(CO)₁₂ remarkably improved the efficiency (entry 9). Various ligands were screened to further improve the yield. Although phosphines completely inhibited the reaction, the addition of chelating N-ligands was beneficial for this transformation (entries 10–15). When phenanthroline was used, the desired product was obtained in 73% yield as a single regioisomer (entry 12). The structure of the product 3a was confirmed by independent synthesis as well as by X-ray crystallography of the p-bromobenzoyl ester of the deprotected alcohol (Scheme 3, Fig. 1). Moreover, this reaction was very sensitive to the solvent. For example, the transformation could proceed in o-xylene and dioxane in lower yields but gave no product in more polar solvents such as DMF (entries 16–18). Different silanes also affected the yields dramatically, as the use of iPr₃SiH, tBuMe₂SiH, PhMe₂SiH and Et₂MeSiH instead of Et₃SiH gave 0, 12, 29 and 61% yields, respectively.

Table 1 Optimization study^a

Entry	Catalyst (mol%)	Ligand	Solvent	Yield^b (%)
a Reaction conditions: 0.25 mmol of 1a, 0.75 mmol of 2a, 0.75 mmol of HSiEt3, indicated amount of catalyst, 0.01 mmol of ligand in 1 mL solvent at 135 °C for 12 h. b Isolated yields. bpy = 2,2′-bipyridine; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine; phen = 1,10-phenanthroline; neocuproine = 2,9-dimethyl-1,10-phenanthroline; bathophen = 4,7-diphenyl-1,10-phenanthroline; DMF = N,N-dimethylformamide.
1	—	—	Benzene	0
2	Mn2(CO)10 (4)	—	Benzene	0
3	Re2CO)10 (4)	—	Benzene	0
4	Ru3(CO)12 (3)	—	Benzene	<5
5	[Rh(COD)Cl]2 (4)	—	Benzene	<5
6	[Ir(COD)Cl]2 (4)	—	Benzene	14
7	[Ir(COD)(OMe)]2 (4)	—	Benzene	<5
8	[Cp*IrCl2]2 (4)	—	Benzene	<5
9	Ir4(CO)12 (2)	—	Benzene	45
10	Ir4(CO)12 (2)	bpy	Benzene	65
11	Ir4(CO)12 (2)	dtbpy	Benzene	70
12	Ir4(CO)12 (2)	phen	Benzene	73
13	Ir4(CO)12 (2)	neocuproine	Benzene	59
14	Ir4(CO)12 (2)	bathophen	Benzene	58
15	Ir4(CO)12 (2)	PPh3	Benzene	<5
16	Ir4(CO)12 (2)	phen	o-Xylene	56
17	Ir4(CO)12 (2)	phen	Dioxane	57
18	Ir4(CO)12 (2)	phen	DMF	<5

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Scheme 3 Determination of the structure 3a.

Fig. 1 ORTEP diagram of 3a′ with 50% thermal ellipsoids.

Synthetic scope

With the optimized condition, we next studied the scope of the aryl aldehydes (Table 2).‡ The reactions of various ortho and para substituted aryl aldehydes gave good yields (entries 2–6). Aryl halides including fluoride, chloride and even bromide were compatible with the reaction conditions, despite their tendency to undergo silylation or dehalogenation reactions (entries 7–9).¹³ Heteroaromatic aldehydes 2j–2l were also suitable substrates (entries 10–12). In general, electron-rich aromatic aldehydes (2f, 2j–2l) gave lower yields, presumably due to their lower electrophilicity. Aliphatic aldehyde (2m) exhibited poor reactivity since it is more electron-rich (entry 13). Conducting the reaction at 2.5 mmol scale did not affect the yield (entry 1).

Table 2 Scope of aryl aldehydes^a

Entry	Ar		Product	Yield^b (%)
a Reaction conditions: 0.25 mmol of 1, 0.75 mmol of aldehyde, 0.75 mmol of HSiEt3, 0.005 mmol of Ir4(CO)12, 0.01 mmol of phen in 1 mL of benzene at 135 °C for 12 h. b Isolated yields. c 2.5 mmol scale.
1	C6H5	2a	3a	73 (72)^c
2	2-MeC6H4	2b	3b	78
3	2,5-Me2C6H3	2c	3c	77
4	2-Naphthyl	2d	3d	72
5	4-MeC6H4	2e	3e	76
6	4-MeOC6H4	2f	3f	57
7	4-FC6H4	2g	3g	74
8	4-ClC6H4	2h	3h	62
9	4-BrC6H4	2i	3i	60
10	2-Benzofuryl	2j	3j	55
11	2-Benzothiophene	2k	3k	54
12	3-Thiophene	2l	3l	68
13	n-Hexyl	2m	3m	<10

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The catalytic system was further applied to functionalize a variety of pyridine derivatives (Table 3). Various 3-arylpyridines (1a–1c) and 3-alkylpyridines (1d, 1e) reacted quite well. However, more electron-donating groups such as methoxyl and benzyloxyl substituents (1f, 1g) slightly decreased the reaction efficiency. To our interest, isoquinoline (1i) showed much better reactivity than quinoline (1h). In all cases, selective functionalization at the meta position of the nitrogen atom was exclusively obtained. When unsubstituted pyridine (1j) was tested, a mixture of mono- and di-functionalized products at meta-position was obtained, indicating that such a meta selectivity was controlled by the intrinsic feature of pyridine rather than the substituent. Although the reaction efficiency of 3,4-disubstituted pyridine (1k) was decreased by the substituent at the C4 position, this steric effect did not completely inhibit the reaction. This stood in contrast with the well known meta-selective C–H borylation and silylation reactions, in which steric bias dominated the regioselectivity.^14,15 For reasons we do not fully understand, the reactions of 2-substituted pyridines such as 2-methylpyridine and 2,6-lutidine gave low yields (<5%) of products.

Table 3 Scope of pyridine derivatives^a

Entry	1	Product	Yield^b (%)
a Reaction conditions: 0.25 mmol of 1, 0.75 mmol of benzaldehyde, 0.75 mmol of HSiEt3, 0.005 mmol of Ir4(CO)12, 0.01 mmol of phen in 1 mL of benzene at 135 °C for 12 h. b Isolated yields.
1			3a, 73
2			3n, 68
3			3o, 66
4			3p, 61
5			3q, 66
6			3r, 53
7			3s, 55
8			3t, 27
9			3u, 62
10			3v, 37
			3v′, 21
11			3w, 31

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Mechanistic studies

In order to gain insight into this novel reaction, mechanistic studies were carried out. We found that, (1) trialkylsilane was essential for the reaction, as no reaction occurred in its absence; (2) C–H silylation of the pyridine derivatives could not be detected at various stages of the reaction (eqn (1)). However, it could be detected in the absence of benzaldehyde, albeit in a very low yield. When norbornene or tert-butylethylene was added instead of benzaldehyde, these hydrogen acceptors did not promote the efficiency of the C–H silylation(eqn (2)).¹⁶ Thus, it is unlikely that benzaldehyde functioned as a hydrogen scavenger for the C–H silylation reaction; (3) the nucleophilic addition of the independently synthesized 3-phenyl-5-(triethylsilyl)pyridine 4 to benzaldehyde could not occur either directly or in the presence of iridium catalyst(eqn (3)); (4) when 3-triethylsilylpyridine was subjected to the standard condition, the desired coupling product was obtained. However, the product resulting from the addition of arylsilane to benzaldehyde was not detected at all (eqn (4)). This suggested that the active catalyst for the addition of a C–H bond to aldehyde was not capable to promote the addition of pyridylsilane to the aldehyde. Together, these results showed that the efficiency of the catalytic C–H silylation process was low,¹⁶ and the reaction of pyridylsilane with aldehyde was infeasible.¹⁷ Therefore, a reaction mechanism involving C–H silylation followed by the addition of the resulting silane to aldehyde is unlikely in the current catalytic system.

One possible explanation of the meta selectivity is the migration of the initially formed C(2)–Ir bond to the C3 position. To see whether the C–H bond at the ortho position was involved in the reaction, we synthesized the D-labeled 3-phenylpyridine and subjected it to the standard reaction condition (eqn (5)). It turned out that there was no significant loss of deuterium at the C2 position, suggesting that the ortho C–H bond was not cleaved during the reaction. Thus, the migration of the iridium from C2 to C3 is unlikely.

It is well known that in the meta-selective aromatic C–H borylation reactions, the bulky boryl metal complex was responsible for the regioselectivity.¹⁴ Analogously, we assumed that a similar silyl iridium complex might be the key intermediate. Therefore, we synthesized a silyl iridium complex according to a recent elegant report by Tilley and co-workers (Scheme 4).^18a

Scheme 4 Preparation of a silyl iridium complex

However, the direct application of this silyl iridium complex to the reaction showed no catalytic activity at all (entry 6, Table 4). This was not surprising since a combination of [Ir(COE)₂Cl]₂ and dtbpy did not catalyze the reaction either (entry 5). Comparing with Ir₄(CO)₁₂, [Ir(COE)₂Cl]₂ lacked the CO ligand and has an additional Cl⁻ ligand. To mimic the standard reaction conditions, we carried out the silyl iridium complex catalyzed reactions either under CO atomosphere (entry 7) or in the presence of silver salt as the halide scavenger (entries 8 and 9). Although an CO atomosphere was not beneficial, the addition of silver triflate successfully promoted the silyl iridium catalyzed reaction in 35% isolated yield (entry 9). This result suggested that a silyl iridium complex might be involved in the reaction mechanism.

Table 4 Catalytic reactions using the silyl iridium complex^a

Entry	Catalyst	Isolated yield (%)
a Reaction conditions: 0.25 mmol of 1, 0.75 mmol of benzaldehyde, 0.75 mmol of HSiEt3, indicated amount of catalyst in 1 mL of benzene at 135 °C for 12 h.
1	2 mol% Ir4(CO)12	45
2	2 mol% Ir4(CO)12 + 8 mol% dtbpy	60
3	4 mol% [Ir(COD)Cl]2	14
4	4 mol% [Ir(COE)2Cl]2	5
5	4 mol% [Ir(COE)2Cl]2 + 8 mol% dtbpy	0
6	4 mol% [(dtbpy)Ir(H)(Cl)(SiEt3)]2	0
7	4 mol% [(dtbpy)Ir(H)(Cl)(SiEt3)]2 + CO (1 atm)	Trace
8	4 mol% [(dtbpy)Ir(H)(Cl)(SiEt3)]2 + 8 mol% AgBF4	Trace
9	4 mol% [(dtbpy)Ir(H)(Cl)(SiEt3)]2 + 8 mol% AgOTf	35

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Based on these results, a catalytic mechanism was proposed in Scheme 5. First, an active silyl iridium catalyst 5, which might contain CO, phenanthroline and/or silyl group as ligands, was generated from the combination of Ir precursor, ligand and silane.¹⁸ Oxidative addition of the pyridyl C–H bond to the low-valent Ir species produced the key intermediate 6. Instead of an unfavorable C–Si bond formation by reductive elimination, the intermediate was intercepted by arylaldehyde through C=O insertion into the Ir–Si bond,¹⁹ affording the pyridyl alkyl iridium species 7. Finally, C–C formation through reductive elimination led to the product 3, along with the generation of an iridium hydride species 8, which reacted with hydrosilane to regenerate the active iridium catalyst. According to the proposed mechanism, several observations could be rationalized. First, hydrosilane was necessary for the reaction since it was required for the formation of the active silyl iridium intermediate in the catalytic cycle.¹⁸ Second, the meta selectivity was induced from the oxidative addition of the pyridyl C–H bond to the iridium silyl species. Such a regioselectivity has been observed in several Ir-catalyzed C–H borylation reactions, in which iridium boryl complexes are similarly responsible for the selectivity.¹¹ It should be pointed out that this analogy might not always hold true since borylation of pyridine at the C2 or C4 position was also observed.^11b,c Finally, the silyl group in the intermediate 6 is oxophilic, thereby promoting the insertion of the benzaldehyde through the formation of a strong Si–O bond.¹⁹ Thus, the insertion of benzaldehyde to a less reactive C–Ir bond (intermediate 7′) followed by O–Si forming reductive elimination might be unfavorable.

Scheme 5 Proposed mechanism.

Conclusions

In conclusion, we have developed an unprecedented Ir-catalyzed meta selective C–H activation of pyridine derivatives and subsequent nucleophilic addition to benzaldehyde promoted by hydrosilane. In this reaction, the unfunctionalized pyridine was used as the Grignard reagent surrogate. Mechanistic studies indicated that a silyl iridium complex might be the active catalytic intermediate. The application of chelating N-ligands provided an opportunity for asymmetric synthesis. Expansion of the substrate scope and further understanding of the reaction mechanism are currently underway in our laboratory.

Acknowledgements

Support of this work by NSFC (No. 20672006, 20821062, 20832002, 20925207, GZ419) and the “973” Project from the MOST of China (2009CB825300) is gratefully acknowledged.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Detailed synthetic procedures and characterization of new compounds. CCDC reference number 773152. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0sc00419g

‡ General procedure for the catalytic addition of pyridine derivatives to aryl aldehydes: To an oven-dried 25 mL Schlenk tube was added Ir₄(CO)₁₂ (5.5 mg, 0.005 mmol) and phenanthroline (1.8 mg, 0.01 mmol). The tube was evacuated and refilled with nitrogen. Then 3-phenylpyridine (38.8 mg, 0.25 mmol), benzaldehyde (79.5 mg, 0.75 mmol) and triethylsilane (87.0 mg, 0.75 mmol) were successively added via syringes under a positive stream of dry nitrogen. After the addition of 1 mL of benzene, the tube was tightly sealed and heated to 135 °C in an oil-bath for 12 h. After cooling to room temperature, the resulting mixture was directly purified by flash chromatography on silica gel eluting with ethyl acetate and petroleum ether.

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